Central versus peripheral effects of muscarinic antagonists: the limitations of quaternary ammonium derivatives.
Central versus peripheral effects of muscarinic antagonists: the limitations of quaternary ammonium derivatives.
复制标题
毒蕈碱拮抗剂的中枢与外周作用：季铵衍生物的局限性。
DOI：
10.1007/bf02245315
复制
发表时间：
1992
影响因子：
3.4
通讯作者：
Sarter,M
中科院分区：
文献类型：
--
作者：
Moore,H;Dudchenko,P;Comer,KS;Bruno,JP;Sarter,M
40多年来，M受体阻滞剂一直是研究中枢胆碱能系统功能的主要工具。随着老年性精神功能障碍的“胆碱能假说”的出现，有关M受体拮抗剂的研究呈指数级增长，现在越来越多的人使用人体进行研究。由于季铵盐衍生物被认为不能越过血脑屏障(Schanker 1962；Innes和Nickerson 1975)，东莨菪碱和阿托品季铵盐衍生物的行为效应完全归因于外周调节事件(例如，Levy等人)。1984年)。然而，之前的研究已经指出了这一理论的重大局限性。例如，Carlton在1962年写道：“在进行目前的实验时，我们假设mea(甲基阿托品)将是阿托品外周效应的完美控制……因此，一方面阿托品的行为效应与另一方面mea之间的任何差异都可以归因于阿托品对中枢神经系统的作用”(Carlton 1962，p586)。虽然等摩尔剂量的甲基阿托品不能完全复制阿托品对回避任务中表现的影响，但卡尔顿显然对这一发现感到困惑，即“MeA和阿托品一样，增强了安非他明的行为影响，并导致脑电类似阿托品的减慢”(Carlton和Didamo 1961，第586页)。甲基化形式很少在使用人类或非人类灵长类动物的研究中进行测试(Broks等人(1988)的研究是一个例外，他们测试了0.6毫克甲基东莨菪碱对完好志愿者的影响；报告表明没有发现任何影响，因此没有提供数据)。对70多项有关抗肌肉碱类药物对次灵长类动物行为影响的研究表明，%的研究没有对三级药物作用的潜在外周成分进行对照，即没有测试四元类似物。在剩下的大多数研究中，
For more than 40 years, muscarinic receptor blockers have served as major tools for investigating the functions of central cholinergic systems. With the advent of the" cholinergic hypothesis" of geriatric mental dysfunctions, research dealing with muscarinic antagonists has exponentially increased, and now is increasingly carried out using human subjects. Because quaternary ammonium derivatives have been suggested not to cross the blood-brain-barrier (Schanker 1962; Innes and Nickerson 1975), the behavioral effects of quaternary ammonium derivatives of scopolamine and atropine have been attributed solely to peripherally mediated events (eg, Levy et al. 1984). However, previous studies have indicated significant limitations of this rationale. For example, Carlton wrote in 1962," At the time the present experiments were conducted, we assumed that MeA (methyl atropine) would be a perfect control for the peripheral effects of atropine.... Therefore, any difference between the behavioral effects of atropine, on the one hand, and MeA, on the other, could be ascribed to the action of atropine on the central nervous system"(Carlton 1962, p 586). While equimolar doses of methyl atropine failed to completely reproduce the effects of atropine on performance in an avoidance task, Carlton was apparently puzzled by the finding that" MeA, like atropine, augmented the behavioral effects of amphetamine and that it produced an atropine-like slowing of the EEG"(Carlton and Didamo 1961, p 586). Methylated forms have rarely been tested in studies using humans or nonhuman primates (an exception is the study by Broks et al.(1988), who tested the effects of 0.6 mg methylscopolamine in intact volunteers; the report indicates that no effects were found and thus data were not presented). A survey of over 70 studies on the behavioral effects of antimuscarinics in subprimate animals indicated that 64% of these studies did not control for potential peripheral components of the effects of tertiary drugs, ie, they did not test quaternary analogues. In the majority of the remaining studies,